Nitrite is a signaling molecule and regulator of gene expression in mammalian tissues

Abstract

Mammalian tissues produce nitric oxide (NO) to modify proteins at heme and sulfhydryl sites, thereby regulating vital cell functions. The majority of NO produced is widely assumed to be neutralized into supposedly inert oxidation products including nitrite (NO2(-)). Here we show that nitrite, also ubiquitous in dietary sources, is remarkably efficient at modifying the same protein sites, and that physiological nitrite concentrations account for the basal levels of these modifications in vivo. We further find that nitrite readily affects cyclic GMP production, cytochrome P450 activities, and heat shock protein 70 and heme oxygenase-1 expression in a variety of tissues. These cellular activities of nitrite, combined with its stability and abundance in vivo, suggest that this anion has a distinct and important signaling role in mammalian biology, perhaps by serving as an endocrine messenger and synchronizing agent. Thus, nitrite homeostasis may be of great importance to NO biology.

Improvement in blood pressure after short-term inorganic nitrate supplementation is attenuated in cigarette smokers compared to non-smoking controls

“…These findings are consistent with several [9,[11][12][13][14][15], but not all [e.g., 68], previous reports of lower blood pressure after NIT in normotensive non-smoking participants. In addition, we observed a significant negative correlation between the change in plasma [NO 2 -] and the change in systolic blood pressure between the PLA and NIT conditions in the non-smokers, consistent with the effects of NO 2 - [28,29] or NO [30,57] on smooth muscle relaxation, and with previous reports of negative correlations between the changes in plasma [NO 2 -] and blood pressure [57].…”

“…NO 2 --rich saliva is then ingested and NO 2 -is further reduced to nitric oxide (NO) and other reactive nitrogen intermediates in the acidic environment of the stomach [26][27]. It is also clear that a portion (in the nM range) of the ingested NO 2 -passes into the systemic circulation [24] where it can impact vascular function directly [28,29] or through its subsequent reduction to NO via a number of NO 2 -reductases [30]. Although mammalian tissues have the capacity to directly metabolise NO 3 - [34], the entero-salivary delivery of NO 3 -to the oral cavity and its subsequent reduction to NO 2 -by lingual anaerobes, are key rate limiting steps of NO 3 -metabolism in mammals [35].…”

Red wine-dependent reduction of nitrite to nitric oxide in the stomach

“…Independently of NOS, accumulating evidence suggest that heme proteins, xanthine oxidoreductase and thiol-containing enzymes may convert nitrite into U NO [2] during ischemic or hypoxic events [3][4][5]. These observations, among others showing that nitrite may regulate cell functions via protein modifications at heme and sulfhydryl sites, have spot nitrite as an endogenous molecule involved in the physiology and therapeutics of the cardiovascular system [6]. In particular, the chemical reduction of inorganic nitrite to U NO has been initially uncovered as a new biologically-relevant mechanism in acidic environments, notably the gastric compartment [7,8].…”

Circulating nitric oxide metabolites and cardiovascular changes in the turtleTrachemys scriptaduring normoxia, anoxia and reoxygenation

“…During normal tissue oxygenation, NO is synthesized from L-arginine and molecular O 2 by a family of enzymes, the nitric oxide synthases (NOSs) (Alderton et al, 2001). However, when O 2 (a substrate for NOS) becomes limiting, nitrite and S-nitrosothiols (RSNO), which are relatively stable in vivo products of NO, function as recyclable sources of NO (Bryan et al, 2005;Hess et al, 2005) and contribute to hypoxic vasodilatation (Crawford et al, 2006;Dalsgaard et al, 2007). The conversion of nitrite to NO may occur non-enzymatically (Zweier et al, 1995) or may be catalysed by a number of enzymes (reviewed by Lundberg et al, 2008;van Faassen et al, 2009), including deoxygenated haemoglobin (Hb) (Cosby et al, 2003).…”